Wearable injector with sterile adhesive patch

ABSTRACT

An adhesive patch for a drug delivery device with a bacteria impermeable sterility margin surrounding an edge surface of the adhesive patch is disclosed, as well as a drug delivery device fixed to such an adhesive patch and a method of assembling a drug delivery device with such an adhesive patch. In some arrangements, the sterility margin is attached to or integral with a lower liner on a lower surface of the adhesive patch. In other arrangements, the sterility margin is attached to or integral with an upper liner on an upper surface of the adhesive patch.

CROSS-REFERENCE TO RELATED APPLICATIONS

The priority benefit of U.S. Provisional Patent Application No.62/547,500, filed Aug. 18, 2017, is claimed and the entire contentsthereof are incorporated by reference herein.

FIELD OF DISCLOSURE

The present disclosure generally relates to wearable drug deliverydevices and, more particularly, to a sterile adhesive patch for awearable drug delivery device.

BACKGROUND

Some drug delivery devices, such as on-body injectors, may betemporarily attached to a patient to deliver a drug via an injectionneedle or some other means over an extended period of time. The drugdelivery device may be attached to the tissue of the patient's abdomen,thigh, arm, or some other portion of the patient's body. In some cases,the drug delivery device may be worn by the patient for several minutesor hours while the drug is injected. For example, viscous drugs,including some biologics, can have long injection times due to the forceneeded to expel them from the drug delivery device. Furthermore, somedrug delivery devices are configured to be attached to the patient at adoctor's office, and then later deliver the drug to the patient when thepatient returns to his or her home. During manufacturing and transportthe bacteria or other harmful micro-organisms may adhere to the exposedsurfaces of the adhesive and transfer to the patient once the drugdelivery device is attached to the patient. This is true even ofrelatively small adhesive surfaces, such as the exposed edge surface atthe perimeter of an adhesive patch created by the thickness of thepatch.

Some drug delivery devices further include a window for viewing andinspection of the drug in order to determine, for example, whetherdelivery of the drug is complete. However, some drugs are photosensitive and can be damaged by exposure to visible light. In order toprotect such drugs, the size of viewing windows in drug delivery deviceshave been minimized or tinted. However, these solutions can make it moredifficult to view the drug.

SUMMARY

In accordance with a first aspect, a drug delivery device includes ahousing having a bottom wall. The drug delivery device also includes anadhesive patch adhered to the bottom wall and having an area containedwithin an outer perimeter, the area having an upper surface, a lowersurface, and an edge surface at the outer perimeter between the uppersurface and the lower surface. Additionally, the drug delivery deviceincludes a bacteria impermeable lower liner on the lower surface and abacteria impermeable sterility margin surrounding the edge surface.

In accordance with a second aspect, an adhesive patch for a drugdelivery device includes an area contained within an outer perimeter,the area having an upper surface, a lower surface, and an edge surfaceat the outer perimeter between the upper surface and the lower surface.The adhesive patch also includes a bacteria impermeable lower liner onthe lower surface and a bacteria impermeable sterility marginsurrounding the edge surface.

In accordance with a third aspect, a method of assembling a drugdelivery device comprises providing an adhesive patch, the adhesivepatch including an area contained within an outer perimeter, the areahaving an upper surface, a lower surface, and an edge surface at theouter perimeter between the upper surface and the lower surface, abacteria impermeable lower liner on the lower surface, and a bacteriaimpermeable sterility margin surrounding the edge surface. The methodfurther includes providing a sub-assembly of a drug delivery devicecomprising an insertion mechanism. Additionally, the method includesadhering the adhesive patch to the drug delivery device.

In some arrangements, the bacteria impermeable sterility margin may beattached to or integral with the lower liner. In other arrangements, theadhesive patch further includes a bacteria impermeable upper liner onthe upper surface, and the sterility margin may be attached to orintegral with the upper liner. In some arrangements, the outer perimeterof the adhesive patch may be pre-cut in a perforated manner to separatefrom the sterility margin. In some arrangements, the sterility marginmay have a width of at least two millimeters. In some arrangements, theupper liner may include a pre-cut first perimeter surrounding a portionof the area configured to be adhered to a drug delivery device. In somearrangements, a hole is provided in the area to allow passage of adelivery member of the drug delivery device.

In some arrangements, the housing includes an interior space and aninsertion mechanism may be disposed within the interior space of thehousing. The insertion mechanism may be activated to move a deliverymember from a retracted position within the housing to a deployedposition extending outside of the housing. A hole may be provided in thearea of the adhesive patch to allow the delivery member to extendoutside of the housing without having to penetrate the adhesive patch.

In some arrangements, the housing may include an interior space and atop wall. A container may be disposed within the interior space, and thetop wall may include a window positioned to allow viewing of thecontainer. The window may include a polarized filter that filters out upto and including 50% of light in the visible range.

In some variations of the method, a hole may be provided in the area ofthe adhesive patch, and the method may include aligning the hole of theadhesive patch with the insertion mechanism of the sub-assembly of thedrug delivery device. In some variations, the method may includesterilizing the adhesive patch and the sub-assembly of the drug deliverydevice. In some variations, the sub-assembly of the drug delivery devicemay further include a container, and the method may include filling thecontainer in a sterile fill line while the container is attached to asubassembly of the drug delivery device. In some variations, the methodfurther includes connecting the sub-assembly of the drug delivery deviceto all remaining parts of the drug delivery device in an environmentthat may or may not be sterile. In some variations, the method furtherincludes sealing the adhesive patch to the sub-assembly of the drugdelivery device to prevent bacteria from entering the sterile regions ofthe adhesive patch, insertion mechanism and drug delivery device. Insome variations, the method further includes sealing the insertionmechanism to the bottom wall to prevent bacteria from entering sterileregions of the adhesive patch, insertion mechanism and drug deliverydevice.

BRIEF DESCRIPTION OF THE DRAWINGS

It is believed that the disclosure will be more fully understood fromthe following description taken in conjunction with the accompanyingdrawings. Some of the drawings may have been simplified by the omissionof selected elements for the purpose of more clearly showing otherelements. Such omissions of elements in some drawings are notnecessarily indicative of the presence or absence of particular elementsin any of the exemplary embodiments, except as may be explicitlydelineated in the corresponding written description. Also, none of thedrawings are necessarily to scale.

FIG. 1 illustrates a schematic cross-sectional view of an embodiment ofa drug delivery device in accordance with principles of the presentdisclosure.

FIG. 2 illustrates a drug delivery device having a viewing window, thedrug delivery device adhered to an adhesive patch, in accordance withprinciples of the present disclosure.

FIG. 3A illustrates an adhesive patch prior to assembly with a drugdelivery device in accordance with principles of the present disclosure.

FIG. 3B illustrates the adhesive patch of FIG. 3A as a portion of anupper liner within a pre-cut first perimeter is removed.

FIG. 3C illustrates the adhesive patch of FIGS. 3A and 3B as having ahole aligned with an insertion mechanism of the drug-delivery device.

FIG. 3D illustrates an exploded view of the assembled adhesive patch anddrug delivery device sub-assembly of FIGS. 3A-3C.

FIG. 4 illustrates removal of a lower liner integral with or attached tothe sterility margin in accordance with principles of the presentdisclosure.

FIG. 5A illustrates removal of a lower liner from an assembled adhesivepatch and drug delivery device in accordance with principles of thepresent disclosure.

FIG. 5B illustrates removal of an upper liner integral with or attachedto the sterility margin of the adhesive patch of FIG. 5A in accordancewith principles of the present disclosure.

DETAILED DESCRIPTION

FIG. 1 is a schematic illustration of one embodiment of a drug deliverydevice 10 fixed to an adhesive patch 100. The drug delivery device 10has a housing 29 with a bottom wall 25 to which the adhesive patch 100is adhered. The adhesive patch 100 has an area 102 contained within anouter perimeter 104. The area 102 has an upper surface 110, a lowersurface 112, and an edge surface 114 at the outer perimeter 104 betweenthe upper surface 110 and the lower surface 112. A bacteria impermeablelower liner 120 is on the lower surface 112. In order to address theissue of bacteria collecting along the edge surface 114, the adhesivepatch 100 advantageously includes a removable bacteria impermeablesterility margin 124. Further details regarding the adhesive patch 100and the bacteria impermeable sterility margin 124 are discussed belowwith respect to FIGS. 2-5B.

Returning to FIG. 1, additional detail regarding on exemplary version ofthe specific drug delivery device 10 incorporated with the adhesivepatch 100 of the present disclosure will be described. Other drugdelivery devices are possible. The drug delivery device 10 may beoperated to subcutaneously or transdermally deliver a drug to a patient.In the illustrated embodiment, the drug delivery device 10 is configuredas a wearable drug delivery device, such as an on-body injector or anambulatory infusion pump, and is releasably attachable to the patient'stissue 11 (e.g., the patient's skin). In other embodiments (notillustrated), the drug delivery device 10 may be configured as apen-type injector, such as an autoinjector or injection pen, which istemporarily held against the patient's tissue 11 over the course of theinjection. The drug delivery device 10 may be configured toautomatically deliver a fixed or a patient/operator-settable dose of thedrug over a controlled or selected period of time. Furthermore, the drugdelivery device 10 may be intended for self-administration by thepatient, or may be operated by a formally trained healthcareprofessional or other caregiver to administer the injection.

Generally, the drug delivery device 10 may include an insertionmechanism 12, a container 14, a fluid pathway assembly 22, a drivemechanism 24, and a controller 26, each of which may be disposed withinan interior space of a main housing 29. An actuator 28 (e.g., auser-depressible button, touchscreen, microphone, etc.) may protrudethrough or otherwise be disposed at an exterior surface of the housing29 and may be configured to initiate operation of the drug deliverydevice 10 by activating, via mechanical and/or electrical means (shownin dotted lines in FIG. 1), the insertion mechanism 12, the fluidpathway assembly 22, the drive mechanism 24, the controller 26, and/orother mechanisms and/or electronics. In embodiments where the actuator28 is a button that is depressed or otherwise physically moved by a useror patient, the actuator 28 may be configured to exert a motive forceneeded to activate the insertion mechanism 12, the fluid pathwayassembly 22, the drive assembly 24, the controller 26, and/or othermechanisms. In such embodiments, the actuator 28 may be physicallyconnected to, either directly or indirectly via a mechanical linkage,the insertion mechanism 12, the drive mechanism 24, the fluid pathwayassembly 22, and/or other mechanisms such that manually depressing orotherwise interacting with the actuator 28 supplies the motive forcenecessary to activate the insertion mechanism 12, the drive mechanism24, the fluid pathway assembly 22, and/or other mechanisms. For example,in some embodiments, manually depressing the actuator 28 may cause thefluid pathway assembly 22 to move towards the stationary container 14,or cause the container 14 to move towards the stationary fluid pathwayassembly 22, and thereby cause a container access needle to penetratethrough a seal member into a reservoir or interior volume of thecontainer 14. Additionally or alternatively, the actuator 28 may operateas an input device that transmits an electrical and/or mechanical signalto the controller 26, which in turn may execute programmableinstructions to control operation of the insertion mechanism 12, thedrive mechanism 24, the fluid pathway assembly 22, and/or othermechanisms. In such embodiments, the controller 26 may include aprocessor (e.g., a microprocessor) and a non-transitory memory forstoring the programmable instructions to be executed by the processor.Furthermore, in such embodiments, the drug delivery device 10 mayinclude an internal actuator (e.g., an electric motor, a pneumatic orhydraulic pump, and/or a source of pressurized gas or liquid) which isseparate from the actuator 28 and which, in response to an electricalcontrol signal received from the controller 26, exerts the motive forceneeded to activate the insertion mechanism 12, the drive mechanism 24,the fluid pathway assembly 22, and/or other mechanisms.

Still referring to FIG. 1, the housing 29 may include a bottom wall 25configured to be releasably attached (e.g., adhered with an adhesive) tothe patient's tissue 11, and a top wall 27 including one or more visualindicators 42 (e.g., lights, graphical displays, etc.) and/or a window35 for viewing the container 14 and a drug 32 contained therein. The oneor more visual indicators 42 may be used to communicate information tothe user about the operational state of the drug delivery device 10and/or the condition of the drug 32. An opening 31 may be formed in thebottom wall 25 to allow extension of a trocar 21 and a hollow cannula 23surrounding the trocar 21 through and across the bottom wall 25. Thebottom surface of the insertion mechanism 12 is attached to the bottomwall 25 and may have a bacteria impermeable seal with the bottom wall25. Additionally, the bottom surface of the insertion mechanism 12 maybe sealed optionally by a pierceable sterile barrier 33, such as apierceable septum to prevent passage of the bacteria from opening 31into the insertion mechanism 12. The pierceable sterile barrier 33 mayextend across the opening 31 to seal the interior of the housing 29prior to use. In some embodiments, the pierceable sterile barrier 33 maybe replaced by a removable sealing member (not illustrated).

The window 35 may be constructed of a transparent or semi-transparentmaterial and generally aligned with the container 14, so as to allow apatient or user of the drug delivery device 10 to inspect the drug 32within the container 14 and/or confirm dose completion. Suitablematerials for the window 35 include, but are not limited to, glassand/or plastic. The location of the window 35 on the exterior of thedrug delivery device 10 may expose the drug 32 to ambient lightincluding sunlight. Some drugs may be sensitive to certain wavelengthsof light and undergo undesirable molecular changes when exposed to suchwavelengths of light. For example, some drugs may be sensitive towavelengths of light in the ultraviolet (UV) range, the visible range,and/or the infrared range. To protect drugs that are primarily sensitiveto light in the UV range and/or the infrared range, a dark tint may beadded to the window 35 and/or the window 35 may be dimensioned to covera relatively small surface area of the housing 29. For drugs that areprimarily sensitive to light in the visible range, it may not benecessary to add a dark tint to the window 35 and/or shrink the size ofthe window 35. Instead, the window 35 may be constructed with apolarized filter. In some embodiments, the polarized filter may be afilm or other coating that is applied to the window 35. In otherembodiments, the polarized filter may be integrated directly into thematerial of the window 35. The polarized filter may allow for viewingand inspection of the drug 32 within the container 14, while filteringout up to and including approximately (e.g., ±10%) 50% of light in thevisible range. In some embodiments, the portion of visible lightfiltered out by the window 35 may fall in a range between approximately(e.g., ±10%) 0-50%, or 10-50%, or 20-50%, or 25-50%, or 0-40%, or 0-30%,or 0-25%, depending on the photosensitivity of the drug 32 and/or theeye strength of the patient population of the drug 32, among otherconsiderations. Adding the polarized filter to the window 35, in lieu ofadding a dark tint to the window 35 and/or shrinking the size of thewindow 35, advantageously protects the drug 35 from light in the visiblerange without substantially compromising the ability of the patient oruser of the drug delivery device 10 to inspect the drug 32 within thecontainer 14.

After the bottom wall 25 of the housing 29 is attached to the patient'stissue 11, the insertion mechanism 12 may be activated to move adelivery member from a retracted position within the housing 29 to adeployed position extending outside of the housing 29. In the presentembodiment, this may include the insertion mechanism 12 inserting atrocar 21 and a hollow cannula 23 surrounding the trocar 21 through thepierceable sterile barrier 33 and into the patient's tissue 11, asillustrated in FIG. 1. Immediately or shortly thereafter, the insertionmechanism 12 may automatically retract the trocar 21, leaving the distalopen end of the cannula 23 inside the patient for subcutaneous deliveryof the drug 32. The trocar 21 may be solid or hollow having a sharpenedend for piercing the patient's skin 11. Furthermore, the trocar 21 maybe made of a material that is more rigid than the cannula 23. In someembodiments, the trocar 21 may be made of metal, whereas the cannula 23may be made of plastic or another polymer. The relative flexibility ofthe cannula 23 may allow it to be disposed subcutaneously within thepatient's tissue 11 for a period of a time without causing pain orsignificant discomfort to the patient. In other embodiments (notillustrated), the trocar 21 and cannula 23 may be omitted, and insteadthe insertion mechanism 12 may insert only a rigid, hollow needle intothe patient for subcutaneous delivery of the drug 32.

In some embodiments, the insertion mechanism 12 may include one or moresprings (e.g., coil springs, torsion springs, etc.) initially retainedin an energized state, and which are released upon depression of theactuator 28 in order to insert the trocar 21 and cannula 23, or hollowneedle, into the patient. Furthermore, retraction of the trocar 21 maybe achieved by the automatic release of another spring after the trocar21 and cannula 23 have been inserted into the patient. Other powersources for insertion and/or retraction are possible, including, forexample, an electric motor, a hydraulic or pneumatic pump, or a canisterthat releases a pressurized gas or pressurized liquid to provideactuation energy.

With continued reference to FIG. 1, the container 14, which in somecontexts may be referred to as a primary container, may include a wall38 with an interior surface 43 defining a reservoir 30 that is filledwith the drug 32 and an exterior surface 47. In some embodiments, thereservoir 30 may be pre-filled with the drug 32 by a drug manufacturerprior to installation of the container 14 in the drug delivery device10. In some embodiments, the container 14 may be rigidly connected tothe housing 29 such that the container 14 cannot move relative to thehousing; whereas, in other embodiments, the container 14 may be slidablyconnected to the housing 29 such that the container 14 can move relativeto the housing 29 during operation of the drug delivery device 10. Thecontainer 14 may have an elongate, barrel-like or cylindrical shapeextending along a longitudinal axis A. In embodiments where the drugdelivery device 10 is configured as an on-body injector, thelongitudinal axis A of the container 14 may be perpendicular orsubstantially perpendicular, or otherwise non-parallel, to a directionin which the insertion mechanism 12 inserts a delivery member such asthe cannula 23 into the patient. This configuration may allow theon-body injector to have a generally planar, low-profile shape that canbe worn by the patient without impeding the patient's movement.Initially, a stopper 34 or other piston member may be positioned in thereservoir 30 at a proximal end 36 of the container 14. The stopper 34may sealingly and slidably engage the interior surface 43 of the wall 38of the container 14, and may be movable relative to the wall 38 of thecontainer 14.

The volume of the drug 32 contained in the reservoir 30 prior todelivery may be: any volume in a range between approximately (e.g.,±10%) 0.5-20 mL, or any volume in a range between approximately (e.g.,±10%) 0.5-10 mL, or any volume in a range between approximately (e.g.,±10%) 1-10 mL, or any volume in a range between approximately (e.g.,±10%) 1-8 mL, or any volume in a range between approximately (e.g.,±10%) 1-5 mL, or any volume in a range between approximately (e.g.,±10%) 1-3.5 mL, or any volume in a range between approximately (e.g.,±10%) 1-3 mL, or any volume in a range between approximately (e.g.,±10%) 1-2.5 mL, or any volume in a range between approximately (e.g.,±10%) 1-2 mL, or any volume equal to or less than approximately (e.g.,±10%) 4 mL, or any volume equal to or less than approximately (e.g.,±10%) 3.5 mL, or any volume equal to or less than approximately (e.g.,±10%) 3 mL, or any volume equal to or less than approximately (e.g.,±10%) 2.5 mL, or any volume equal to or less than approximately (e.g.,±10%) 2 mL, or any volume equal to or less than approximately (e.g.,±10%) 1.5 mL, or any volume equal to or less than approximately (e.g.,±10%) 1 mL. The reservoir 30 may be completely or partially filled withthe drug 32. The drug 32 may be one or more of the drugs describedbelow, such as, for example, a granulocyte colony-stimulating factor(G-CSF), a PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)specific antibody, a sclerostin antibody, or a calcitonin gene-relatedpeptide (CGRP) antibody.

During operation of the drug delivery device 10, the drive mechanism 24may push the stopper 34 along the longitudinal axis A from the proximalend 36 of the container 14 to a distal end 37 of the container 14 inorder to expel the drug 32 from the container 14. In some embodiments,the drive mechanism 24 may include one or more springs (e.g., coilsprings, torsion springs, etc.) initially retained in an energizedstate, and which are released upon depression of the actuator 28.Following their release, the spring(s) may expand or contract to movethe stopper 34 through the reservoir 30 along the longitudinal axis Afrom the proximal end 36 of the container 14 to the distal end 37 of thecontainer 14. In other embodiments, the drive mechanism 24 may includean electric motor (not illustrated) which rotates a gear mechanism,including for example one or more sprocket gears, to cause axial motionof the stopper 34 through the reservoir 30. In still furtherembodiments, the drive mechanism 24 may include both an electric motorand spring(s), wherein the electric motor regulates expansion of thespring(s) via a tether or pulley system. In still further embodiments,the drive mechanism 24 may include a canister that releases apressurized gas or pressurized liquid to provide actuation energy.

Still referring to FIG. 1, the fluid pathway assembly 22 may beconfigured to establish fluid communication between the container 14 andthe insertion mechanism 12 via a sterile fluid flow path duringoperation of the drug delivery device 10. Prior to use of the drugdelivery device 10, the fluid pathway assembly 22 may not be in fluidcommunication with the container 14. During setup of the drug deliverydevice 10, or during the initial stages of operation of the drugdelivery device 10 prior to drug delivery, the user may manually, or thedrug delivery device 10 may automatically, enable, connect, or open thenecessary connections to establish fluid communication between thecontainer 14 and the fluid pathway assembly 22. Subsequently, the drivemechanism 24 may move the stopper 34 in the distal direction to forcethe drug 32 stored in the container 14 through the sterile fluid flowpath of the fluid pathway assembly 22 and into the cannula 23 or needleor other delivery member of the insertion mechanism 12 for subcutaneousdelivery to the patient.

In some embodiments, the fluid pathway assembly 22 may be rigidlyconnected to the housing 29 such that the fluid pathway assembly 22cannot move relative to the housing; whereas, in other embodiments, thefluid pathway assembly 22 may be slidably or moveably connected to thehousing 29 such that the fluid pathway assembly 22 can move relative tothe housing 29 during operation of the drug delivery device 10. In theformer embodiments, the container 14 may be slidably or moveablyconnected to the housing 29 and such that the seal member 40 can bemoved toward and pierced by the point 63 of the stationarily arrangedcontainer access needle 60 of the fluid pathway assembly 22. In thelatter embodiments, the container 14 may be stationarily positionedwhile the fluid pathway assembly 22 is moved toward the container 14,causing the point 63 of the container access needle 60 to pierce throughthe seal member 40 and access the reservoir 30.

The fluid pathway assembly 22 may include a first end 44 connected tothe container 14, a second end 48 connected to the insertion mechanism12, and a fluid passage 50 extending between the first end 44 and thesecond end 48. As described in more detail below, in some embodimentsthe first end 44 of the fluid pathway assembly 22 may be connected tothe container 14 via a clip member 53. The fluid passage 50 may besterilized, and may be partially or entirely made of a flexible tubing52. Initially, there may be slack in the flexible tubing 52 to allow thefluid pathway assembly 22 to move relative to the housing 29 and/or toallow components of the insertion mechanism 12 to which the fluidpathway assembly 22 is attached to move relative to the housing 29. Insome embodiments, the fluid passage 50 may include a rigid fluidrestrictor element (not illustrated) in addition to the flexible tubing52. The fluid restrictor element may have a smaller inner diameter thanthat of the flexible tubing 52 in order to regulate the flow rate of thedrug 32 as it passes through the fluid pathway assembly 22. Furthermore,the fluid restrictor element may be made of a more rigid material thanthe flexible tubing 52. For example, the fluid restrictor element madebe made of metal, whereas the flexible tubing 52 may be made of apolymeric material such as plastic.

Still referring to FIG. 1, the first end 44 of the fluid pathwayassembly 22 may include the container access needle 60 and an overmoldmember 62. In general, the overmold member 62 may serve as a mountingmember or connection hub for the container access needle 60 and providea portion of the container access needle 60 which does not access thereservoir 30 with an enlarged outer dimension, such as an enlarged outerdiameter. The container access needle 60 may have a sharpened end orpoint 63, corresponding to a proximal end of the container access needle60, and a distal end 64 in fluid communication with the fluid passage50. In the illustrated embodiment, the container access needle 60 has abend such that the point 63 of the container access needle 60 may beaxially aligned with the longitudinal axis A of the container 14 whereasthe distal end 64 of the container access needle 60 may be perpendicularor otherwise non-parallel to the longitudinal axis A of the container14. The overmold member 62 may cover a length of the container accessneedle 60, including the bend, with the point 63 of the container accessneedle 60 protruding outwardly from a proximal end 65 of the overmoldmember 62. As shown in FIG. 1, a distal end 66 of the overmold member 62may include a mouth or opening that allows an end of the flexible tubing52 to be inserted into the overmold member 62. In alternativeembodiments, the distal end 66 of the overmold member 62 may be insertedinto an opening formed in the end of the flexible tubing 52.

The container access needle 60 may possess a hollow, tubular shape withone or more openings at each of the point 63 and the distal end 64. Thecontainer access needle 60 made be constructed of a rigid materialincluding, but not limited to, metal (e.g., stainless steel) and/orplastic. In some embodiments, the overmold member 62 may be constructedof a different material than the container access needle 60 such thatthe overmold member 62 and the container access needle 60 are separate,but rigidly connected, components. In some embodiments, the overmoldmember 62 may be constructed of a rigid plastic material whereas thecontainer access needle 60 is constructed of metal. In otherembodiments, the overmold member 62 and the container access needle 60may be made of the same material such that they form a single, unitaryone-piece structure.

Generally, the overmold member 62 may have a sleeve-like or tubularshape that surrounds a length of the container access needle 60. Theovermold member 62 may be fixedly or rigidly connected to the needle 60such that the overmold member 62 and the needle 60 can move togetherjointly as a single unit or structure. Stated another way, the overmoldmember 62 may be fixedly or rigidly connected to the container accessneedle 60 such that the needle 60 is prevented from moving relative tothe overmold member 62. At least the proximal end 65 of the overmoldmember 62 may flushly cover a length of the container access needle 60with no gaps therebetween. As seen in FIG. 1, there may be a gap betweenthe distal end 66 of the overmold member 62 and the container accessneedle 60 to form the mouth or opening for receiving the flexible tubing52. In alternative embodiments, no mouth or opening may be formed in thedistal end 66 of the overmold member 62 such that the no gap existsbetween the distal end 66 of the overmold member 62 and the containeraccess needle 60.

As shown in FIG. 1, prior to activation of the drug delivery device 10(e.g., in a storage state), the overmold member 62 may define anenclosed clean space 68 between the overmold member 62 and the sealmember 40. In some embodiments, the enclosed clean space 68 may be anempty space which has been sterilized and which may or may not be avacuum. In other embodiments, the enclosed clean space may be a spacefilled with a gaseous or liquid sterilizing agent. A variety ofconfigurations are possible for defining the boundary of the enclosedclean space 68; however, at a minimum, the boundary of the enclosedclean space 68 may be defined by a surface of the overmold member 62 anda surface of the seal member 40.

As shown in FIG. 1, prior to activation of the drug delivery device 10,the container access needle 60 may be arranged in a storage positionwith its point 63 disposed exterior to the reservoir 30. In someembodiments, in the storage position, the point 63 of the containeraccess needle 60 may be disposed in the enclosed clean space 68, therebyinhibiting or preventing contamination of the point 63 of the containeraccess needle 60. In other embodiments, in the storage position, thepoint 63 of the container access needle 60 may be disposed partiallythrough the seal member 40 such that the point 63 is embedded within thematerial of the seal member 40. Embedding the point 63 within thematerial of the seal member 40 may inhibit or prevent contamination ofthe point 63. In such embodiments, the enclosed clean space 68 may befilled with a gaseous or liquid sterilizing agent, such that duringmanufacturing, when the point 63 is inserted through the enclosed cleanspace 68, the point 63 is sterilized by the gaseous or liquidsterilizing agent.

In order to restrain the container access needle 60 in the storageposition prior to activation of the drug delivery device 10, the clipmember 53 may frictionally engage the exterior surface of the overmoldmember 62. Accordingly, the clip member 53 may resist movement of theovermold member 62 in a direction toward and/or away from the sealmember 40.

Upon activation of the drug delivery device 10, the container accessneedle 60 may be moved from the storage position to a delivery position,where the point 63 is disposed through the proximal end surface 73 ofthe seal member 40 into the reservoir 30, thereby establishing fluidcommunication with the drug 32. In some embodiments, the actuator 28 maybe mechanically linked or connected, directly or indirectly, to thecontainer access needle 60 such that manual depression of the actuator28 provides the motive force necessary for moving the container accessneedle 60 from the storage position to the delivery position 62. Inother embodiments, as described above, an energized actuator (including,e.g., an electric motor, a pneumatic or hydraulic pump, and/or a sourceof pressurized gas or liquid) may be activated in response to a user'sdepression of the actuator 28 and provide the motive force necessary formoving the container access needle 60 from the storage position to thedelivery position.

Where appropriate, any of the above-described sub-assemblies,mechanisms, components, features, functionalities, methods ofmanufacture, methods of use, and other aspects of the drug deliverydevice 10 may be replaced with and/or combined with any of thesub-assemblies, mechanisms, components, features, functionalities,methods of manufacture, methods of use, and other aspects of the drugdelivery devices described in some or all of the following documents,each of which is hereby incorporated by reference in its entirety forall purposes: U.S. Pat. No. 9,061,097; U.S. Patent ApplicationPublication No. 2017/0124284; U.S. Patent Application Publication No.2017/0119969; U.S. Patent Application Publication No. 2017/0098058; U.S.Patent Application Publication No. 2017/0124285; U.S. Patent ApplicationPublication No. 2017/0103186; U.S. Provisional Patent Application No.62/460,501 entitled “INSERTION MECHANISM FOR DRUG DELIVERY DEVICE”; U.S.Provisional Patent Application No. 62/469,226 entitled “INSERTIONMECHANISM FOR DRUG DELIVERY DEVICE”; U.S. Provisional Patent ApplicationNo. 62/468,190 entitled “INSERTION MECHANISM AND METHOD OF INSERTING ANEEDLE OF A DRUG DELIVERY DEVICE”; U.S. Provisional Patent ApplicationNo. 62/460,559 entitled “DRUG DELIVERY DEVICE WITH STERILE FLUIDFLOWPATH AND RELATED METHOD OF ASSEMBLY”; U.S. Provisional PatentApplication No. 62/294,842 entitled “DRUG DELIVERY DEVICE, METHOD OFMANUFACTURE, AND METHOD OF USE”; U.S. Provisional Patent Application No.62/297,718 entitled “DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, ANDMETHOD OF USE”; U.S. Provisional Patent Application No. 62/320,438entitled “DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OFUSE”; International Patent Application No. PCT/US2017/017627 entitled“DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE”; andInternational Patent Application No. PCT/US2017/026524 entitled “DRUGDELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE”.

Turning to FIG. 2, the drug delivery device 10 is depicted having thewindow 35 for viewing the container 14 and the drug 32 contained therein(shown in FIG. 1). The drug delivery device 10 is adhered or otherwisefixed to an adhesive patch 100. The adhesive patch 100 has an area 102contained within an outer perimeter 104. A portion of the area 102 isfixed to the bottom wall 25 (covered in FIG. 2) of the housing 29 of thedrug delivery device 10. The bottom wall 25 has an outer boundary 132.The outer perimeter 104 of the adhesive patch 100 extends beyond theouter boundary 132 of the bottom wall 25.

Turning to FIG. 3A, the adhesive patch 100 is shown prior to being fixedto the drug delivery device 10. The adhesive patch 100 has an uppersurface 110 (not visible in FIG. 3A) covered by a bacteria impermeableupper liner 116 and a lower surface 112 (not visible in FIG. 3A) coveredby a bacterial impermeable lower liner 120. As will be described morefully below, a bacteria impermeable sterility margin 124 surrounds anedge surface 114 (see, FIG. 4; not visible in FIG. 3A) extending betweenthe upper surface 110 and the lower surface 112. The upper liner 116 hasa first perimeter 118 surrounding a portion of the adhesive patch 100that will be adhered to the drug delivery device 10. The upper liner 116is pre-cut at the first perimeter 118. In some arrangements, the upperliner 116 may be pre-cut at the first perimeter 118 in a perforatedmanner. In some arrangements, the first perimeter 118 does not extendbeyond the outer boundary 132 of the bottom wall 25 (shown in FIG. 2) inorder to prevent exposure of adhesive on upper surface 110.

As shown in FIG. 3B, to assemble the adhesive patch 100 to the drugdelivery device 10, the portion of the upper liner 116 that is withinthe first perimeter 118 is removed. A hole 108 in the adhesive patch 100is then visible and exposed. Turning to FIG. 3C, the hole 108 is alignedwith the insertion mechanism 12 (shown in FIG. 1) of the drug deliverydevice 100 in order to allow the delivery member (shown in FIG. 1) ofthe insertion mechanism 12 to extend to a deployed position withouthaving to penetrate the adhesive patch 100. The portion of the area 102configured to be adhered to the drug delivery device 100 is then adheredto a sub-assembly of the drug delivery device 10. For purposes of thisdisclosure, a “sub-assembly” may refer to a portion or the entirety ofthe drug delivery device 10. The adhesion is completed such that theportion of the area 102 adhered to the drug delivery device 100 providesa seal to prevent bacteria from entering hole 108. The adhesive patch100 and the sub-assembly of the drug delivery device 10 are thensterilized. The sub-assembly of the drug delivery device 100 comprises acontainer (shown in FIG. 1), which is filled in a sterile fill line.After that, all remaining parts of the drug delivery device 10 may beconnected to the sub-assembly in an environment that may or may notnecessarily be sterile. While the patch 100 has been described asincluding the hole 108, other configurations of the patch 100 may notinclude the hole 108 and instead the delivery member may penetratedirectly through the patch 100.

FIG. 3D shows the adhesive patch 100 and drug delivery device 10 ofFIGS. 3A-3C in an exploded view after assembly has been completed forpurposes of shipment and storage but prior to use by a patient orcaregiver. At the top is the drug delivery device 10. Below the drugdelivery device 10 is the upper liner 116 with the portion of the upperliner 116 within the first perimeter 118 removed. The adhesive patch 100having area 102 within outer perimeter 104 is shown below the upperliner 116. The adhesive patch 100 has an upper surface 110, a lowersurface 112, and an edge surface 114 (see FIG. 4; not visible in FIG.3D). The hole 108 is provided in the area 102 of the adhesive patch 100in this version. Below that, the lower liner 120 is shown. The sterilitymargin 124 is a frame-like structure that surrounds the edge surface 114and includes a sealing edge 115 (see, e.g., FIGS. 3D and 4) that forms aseal therewith to reduce and/or prevent contamination. In thearrangement depicted in FIG. 3D, the sterility margin 124 is attached toand is integral with the patch 100 by way of a perforated seam or otherdetachable coupling system connecting the edge surface 114 and thesealing surface 115. In other versions, the sealing edge 115 of thesterility margin 124 may not be physically coupled to the edge surface114, but rather, simply abutted against the edge surface 114 to protectthe edge surface 114 from contamination or exposure to contaminantsuntil after the margin 124 has been removed. In FIG. 3D, the contactbetween the sterility margin 124 and the upper liner 116 and also thecontact between the sterility margin 124 and the lower liner 120 arebacteria impermeable and detachable. In other arrangements discussedbelow relative to FIGS. 4, 5A, and 5B, the sterility margin 124 can beintegral with or permanently attached to either the upper liner 116 orthe lower liner 120. The sterility margin 124 generally has a width W ofat least 2 mm in order to facilitate its removal. Sterility margin 124can be simply the outer area of the adhesive patch 100 that is precut orperforated at a width W of at least 2 mm.

FIG. 4 shows one version of the lower liner 120 and sterility margin124, whereby they can be removed at the same time as the drug deliverydevice 110 is prepared for use. In this arrangement, the sterilitymargin 124 is attached to or integral with the lower liner 120. Forexample, the sterility margin 124 may be bonded with adhesive,ultrasonically welded, or otherwise connected to the lower liner 120. Inone version, the sterility margin 124 may be constructed as a singleunit and of the same material as the lower liner 120. The lower liner120 and the sterility margin 124 are pulled away from the adhesive patch100 as a unitary piece and with sufficient force to break any connectionor attraction between the sealing edge 115 of the sterility margin 124and the edge surface 114, thereby exposing the uncontaminated edgesurface 114. In other arrangements, such as that depicted in FIG. 3D,the lower liner 120 and the sterility margin 124 may be removedseparately because the sterility margin 124 is not part of the lowerliner 120 but part of the patch 100. Once the lower liner 120 isremoved, the uncontaminated lower surface 112 (not visible in FIG. 4) ofthe adhesive patch 100 is exposed. Once the sterility margin 124 isremoved, the uncontaminated edge surface 114 of the adhesive patch 100is exposed. Adhesive on the lower surface 112 of the patch 100 enablesthe drug delivery device 10 to be secured to the patient's tissue 11 (asshown in FIG. 1).

FIGS. 5A-5B show an alternative arrangement in which the sterilitymargin 124 is attached to or integral with the upper liner 116. Thesterility margin 124 may, for example, be bonded with adhesive,ultrasonically welded, or otherwise connected to the upper liner 116.With this arrangement, two steps are necessary to prepare the deliverydevice 10 for use. First, as shown in FIG. 5A, the lower liner 120 canbe pulled away from the adhesive patch 100 in order to expose the lowersurface (not visible in FIG. 5A) of the adhesive patch 100. Second, asshown in FIG. 5B, the upper liner 116 and sealing edge 115 of thesterility margin 124 can be pulled away from the adhesive patch 100 andover the drug delivery device 10. In other versions, the upper liner 116and sterility margin 124 can be removed before removing the lower liner120. Regardless, once the sterility margin 124 and upper liner 116 areremoved, the edge surface 114 and upper surface 110 of the adhesivepatch 100 are exposed. Adhesive on the exposed lower surface 112 enablesthe drug delivery device 100 to be secured to the patient's tissue 11(as shown in FIG. 1).

Drug Information

As mentioned above, the container may be filled with a drug. This drugmay be any one or combination of the drugs listed below, with the caveatthat the following list should neither be considered to be all inclusivenor limiting.

For example, the syringe may be filled with colony stimulating factors,such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agentsinclude, but are not limited to, Neupogen® (filgrastim) and Neulasta®(pegfilgrastim). In various other embodiments, the syringe may be usedwith various pharmaceutical products, such as an erythropoiesisstimulating agent (ESA), which may be in a liquid or a lyophilized form.An ESA is any molecule that stimulates erythropoiesis, such as Epogen®(epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta),Mircera® (methyoxy polyethylene glycol-epoetin beta), Hematide®,MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta),Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal,Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetintheta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetinzeta, epoetin theta, and epoetin delta, as well as the molecules orvariants or analogs thereof as disclosed in the following patents orpatent applications, each of which is herein incorporated by referencein its entirety: U.S. Pat. Nos. 4,703,008; 5,441,868; 5,547,933;5,618,698; 5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422;5,986,047; 6,583,272; 7,084,245; and 7,271,689; and PCT Publication Nos.WO 91/05867; WO 95/05465; WO 96/40772; WO 00/24893; WO 01/81405; and WO2007/136752.

An ESA can be an erythropoiesis stimulating protein. As used herein,“erythropoiesis stimulating protein” means any protein that directly orindirectly causes activation of the erythropoietin receptor, forexample, by binding to and causing dimerization of the receptor.Erythropoiesis stimulating proteins include erythropoietin and variants,analogs, or derivatives thereof that bind to and activate erythropoietinreceptor; antibodies that bind to erythropoietin receptor and activatethe receptor; or peptides that bind to and activate erythropoietinreceptor. Erythropoiesis stimulating proteins include, but are notlimited to, epoetin alfa, epoetin beta, epoetin delta, epoetin omega,epoetin iota, epoetin zeta, and analogs thereof, pegylatederythropoietin, carbamylated erythropoietin, mimetic peptides (includingEMP1/hematide), and mimetic antibodies. Exemplary erythropoiesisstimulating proteins include erythropoietin, darbepoetin, erythropoietinagonist variants, and peptides or antibodies that bind and activateerythropoietin receptor (and include compounds reported in U.S.Publication Nos. 2003/0215444 and 2006/0040858, the disclosures of eachof which is incorporated herein by reference in its entirety) as well aserythropoietin molecules or variants or analogs thereof as disclosed inthe following patents or patent applications, which are each hereinincorporated by reference in its entirety: U.S. Pat. Nos. 4,703,008;5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078;5,773,569; 5,955,422; 5,830,851; 5,856,298; 5,986,047; 6,030,086;6,310,078; 6,391,633; 6,583,272; 6,586,398; 6,900,292; 6,750,369;7,030,226; 7,084,245; and 7,217,689; U.S. Publication Nos. 2002/0155998;2003/0077753; 2003/0082749; 2003/0143202; 2004/0009902; 2004/0071694;2004/0091961; 2004/0143857; 2004/0157293; 2004/0175379; 2004/0175824;2004/0229318; 2004/0248815; 2004/0266690; 2005/0019914; 2005/0026834;2005/0096461; 2005/0107297; 2005/0107591; 2005/0124045; 2005/0124564;2005/0137329; 2005/0142642; 2005/0143292; 2005/0153879; 2005/0158822;2005/0158832; 2005/0170457; 2005/0181359; 2005/0181482; 2005/0192211;2005/0202538; 2005/0227289; 2005/0244409; 2006/0088906; and2006/0111279; and PCT Publication Nos. WO 91/05867; WO 95/05465; WO99/66054; WO 00/24893; WO 01/81405; WO 00/61637; WO 01/36489; WO02/014356; WO 02/19963; WO 02/20034; WO 02/49673; WO 02/085940; WO03/029291; WO 2003/055526; WO 2003/084477; WO 2003/094858; WO2004/002417; WO 2004/002424; WO 2004/009627; WO 2004/024761; WO2004/033651; WO 2004/035603; WO 2004/043382; WO 2004/101600; WO2004/101606; WO 2004/101611; WO 2004/106373; WO 2004/018667; WO2005/001025; WO 2005/001136; WO 2005/021579; WO 2005/025606; WO2005/032460; WO 2005/051327; WO 2005/063808; WO 2005/063809; WO2005/070451; WO 2005/081687; WO 2005/084711; WO 2005/103076; WO2005/100403; WO 2005/092369; WO 2006/50959; WO 2006/02646; and WO2006/29094.

Examples of other pharmaceutical products for use with the device mayinclude, but are not limited to, antibodies such as Vectibix®(panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); otherbiological agents such as Enbrel® (etanercept, TNF-receptor/Fc fusionprotein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF,hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such asSensipar® (cinacalcet). The device may also be used with a therapeuticantibody, a polypeptide, a protein or other chemical, such as an iron,for example, ferumoxytol, iron dextrans, ferric glyconate, and ironsucrose. The pharmaceutical product may be in liquid form, orreconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins setforth below, including fusions, fragments, analogs, variants orderivatives thereof:

OPGL specific antibodies, peptibodies, and related proteins, and thelike (also referred to as RANKL specific antibodies, peptibodies and thelike), including fully humanized and human OPGL specific antibodies,particularly fully humanized monoclonal antibodies, including but notlimited to the antibodies described in PCT Publication No. WO 03/002713,which is incorporated herein in its entirety as to OPGL specificantibodies and antibody related proteins, particularly those having thesequences set forth therein, particularly, but not limited to, thosedenoted therein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including theOPGL specific antibodies having either the light chain of SEQ ID NO:2 asset forth therein in FIG. 2 and/or the heavy chain of SEQ ID NO:4, asset forth therein in FIG. 4, each of which is individually andspecifically incorporated by reference herein in its entirety fully asdisclosed in the foregoing publication;

Myostatin binding proteins, peptibodies, and related proteins, and thelike, including myostatin specific peptibodies, particularly thosedescribed in U.S. Publication No. 2004/0181033 and PCT Publication No.WO 2004/058988, which are incorporated by reference herein in theirentirety particularly in parts pertinent to myostatin specificpeptibodies, including but not limited to peptibodies of the mTN8-19family, including those of SEQ ID NOS:305-351, including TN8-19-1through TN8-19-40, TN8-19 con1 and TN8-19 con2; peptibodies of the mL2family of SEQ ID NOS:357-383; the mL15 family of SEQ ID NOS:384-409; themL17 family of SEQ ID NOS:410-438; the mL20 family of SEQ IDNOS:439-446; the mL21 family of SEQ ID NOS:447-452; the mL24 family ofSEQ ID NOS:453-454; and those of SEQ ID NOS:615-631, each of which isindividually and specifically incorporated by reference herein in theirentirety fully as disclosed in the foregoing publication;

IL-4 receptor specific antibodies, peptibodies, and related proteins,and the like, particularly those that inhibit activities mediated bybinding of IL-4 and/or IL-13 to the receptor, including those describedin PCT Publication No. WO 2005/047331 or PCT Application No.PCT/US2004/37242 and in U.S. Publication No. 2005/112694, which areincorporated herein by reference in their entirety particularly in partspertinent to IL-4 receptor specific antibodies, particularly suchantibodies as are described therein, particularly, and withoutlimitation, those designated therein: L1H1; L1H2; L1H3; L1H4; L1H5;L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5;L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12; L2H13; L2H14; L3H1; L4H1;L5H1; L6H1, each of which is individually and specifically incorporatedby reference herein in its entirety fully as disclosed in the foregoingpublication;

Interleukin 1-receptor 1 (“IL1-R1”) specific antibodies, peptibodies,and related proteins, and the like, including but not limited to thosedescribed in U.S. Publication No. 2004/097712, which is incorporatedherein by reference in its entirety in parts pertinent to IL1-R1specific binding proteins, monoclonal antibodies in particular,especially, without limitation, those designated therein: 15CA, 26F5,27F2, 24E12, and 10H7, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe aforementioned publication;

Ang2 specific antibodies, peptibodies, and related proteins, and thelike, including but not limited to those described in PCT PublicationNo. WO 03/057134 and U.S. Publication No. 2003/0229023, each of which isincorporated herein by reference in its entirety particularly in partspertinent to Ang2 specific antibodies and peptibodies and the like,especially those of sequences described therein and including but notlimited to: L1(N); L1(N) WT; L1(N) 1K WT; 2×L1(N); 2×L1(N) WT; Con4 (N),Con4 (N) 1K WT, 2×Con4 (N) 1K; L1C; L1C 1K; 2×L1C; Con4C; Con4C 1K;2×Con4C 1K; Con4-L1 (N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N);TN8-14 (N); Con 1 (N), also including anti-Ang 2 antibodies andformulations such as those described in PCT Publication No. WO2003/030833 which is incorporated herein by reference in its entirety asto the same, particularly Ab526; Ab528; Ab531; Ab533; Ab535; Ab536;Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551; Ab553; Ab555; Ab558;Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12;AbIA1; AbIF; AbIK, AbIP; and AbIP, in their various permutations asdescribed therein, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing publication;

NGF specific antibodies, peptibodies, and related proteins, and the likeincluding, in particular, but not limited to those described in U.S.Publication No. 2005/0074821 and U.S. Pat. No. 6,919,426, which areincorporated herein by reference in their entirety particularly as toNGF-specific antibodies and related proteins in this regard, includingin particular, but not limited to, the NGF-specific antibodies thereindesignated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11, each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing publication;

CD22 specific antibodies, peptibodies, and related proteins, and thelike, such as those described in U.S. Pat. No. 5,789,554, which isincorporated herein by reference in its entirety as to CD22 specificantibodies and related proteins, particularly human CD22 specificantibodies, such as but not limited to humanized and fully humanantibodies, including but not limited to humanized and fully humanmonoclonal antibodies, particularly including but not limited to humanCD22 specific IgG antibodies, such as, for instance, a dimer of ahuman-mouse monoclonal hLL2 gamma-chain disulfide linked to ahuman-mouse monoclonal hLL2 kappa-chain, including, but limited to, forexample, the human CD22 specific fully humanized antibody inEpratuzumab, CAS registry number 501423-23-0;

IGF-1 receptor specific antibodies, peptibodies, and related proteins,and the like, such as those described in PCT Publication No. WO06/069202, which is incorporated herein by reference in its entirety asto IGF-1 receptor specific antibodies and related proteins, includingbut not limited to the IGF-1 specific antibodies therein designatedL1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11,L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20,L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29,L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38,L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47,L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments andderivatives thereof, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing publication;

Also among non-limiting examples of anti-IGF-1R antibodies for use inthe methods and compositions of the present disclosure are each and allof those described in:

(i) U.S. Publication No. 2006/0040358 (published Feb. 23, 2006),2005/0008642 (published Jan. 13, 2005), 2004/0228859 (published Nov. 18,2004), including but not limited to, for instance, antibody 1A (DSMZDeposit No. DSM ACC 2586), antibody 8 (DSMZ Deposit No. DSM ACC 2589),antibody 23 (DSMZ Deposit No. DSM ACC 2588) and antibody 18 as describedtherein;

(ii) PCT Publication No. WO 06/138729 (published Dec. 28, 2006) and WO05/016970 (published Feb. 24, 2005), and Lu et al. (2004), J. Biol.Chem. 279:2856-2865, including but not limited to antibodies 2F8, A12,and IMC-A12 as described therein;

(iii) PCT Publication No. WO 07/012614 (published Feb. 1, 2007), WO07/000328 (published Jan. 4, 2007), WO 06/013472 (published Feb. 9,2006), WO 05/058967 (published Jun. 30, 2005), and WO 03/059951(published Jul. 24, 2003);

(iv) U.S. Publication No. 2005/0084906 (published Apr. 21, 2005),including but not limited to antibody 7C10, chimaeric antibody 07010,antibody h7C10, antibody 7H2M, chimaeric antibody *7C10, antibody GM607, humanized antibody 7C10 version 1, humanized antibody 7C10 version2, humanized antibody 7C10 version 3, and antibody 7H2HM, as describedtherein;

(v) U.S. Publication Nos. 2005/0249728 (published Nov. 10, 2005),2005/0186203 (published Aug. 25, 2005), 2004/0265307 (published Dec. 30,2004), and 2003/0235582 (published Dec. 25, 2003) and Maloney et al.(2003), Cancer Res. 63:5073-5083, including but not limited to antibodyEM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1,huEM164 v1.2, and huEM164 v1.3 as described therein;

(vi) U.S. Pat. No. 7,037,498 (issued May 2, 2006), U.S. Publication Nos.2005/0244408 (published Nov. 30, 2005) and 2004/0086503 (published May6, 2004), and Cohen, et al. (2005), Clinical Cancer Res. 11:2063-2073,e.g., antibody CP-751,871, including but not limited to each of theantibodies produced by the hybridomas having the ATCC accession numbersPTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, andantibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, asdescribed therein;

(vii) U.S. Publication Nos. 2005/0136063 (published Jun. 23, 2005) and2004/0018191 (published Jan. 29, 2004), including but not limited toantibody 19D12 and an antibody comprising a heavy chain encoded by apolynucleotide in plasmid 15H12/19D12 HCA (γ4), deposited at the ATCCunder number PTA-5214, and a light chain encoded by a polynucleotide inplasmid 15H12/19D12 LCF (κ), deposited at the ATCC under numberPTA-5220, as described therein; and

(viii) U.S. Publication No. 2004/0202655 (published Oct. 14, 2004),including but not limited to antibodies PINT-6A1, PINT-7A2, PINT-7A4,PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3,PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2,PINT-12A3, PINT-12A4, and PINT-12A5, as described therein; each and allof which are herein incorporated by reference in their entireties,particularly as to the aforementioned antibodies, peptibodies, andrelated proteins and the like that target IGF-1 receptors;

B-7 related protein 1 specific antibodies, peptibodies, related proteinsand the like (“B7RP-1,” also is referred to in the literature as B7H2,ICOSL, B7h, and CD275), particularly B7RP-specific fully humanmonoclonal IgG2 antibodies, particularly fully human IgG2 monoclonalantibody that binds an epitope in the first immunoglobulin-like domainof B7RP-1, especially those that inhibit the interaction of B7RP-1 withits natural receptor, ICOS, on activated T cells in particular,especially, in all of the foregoing regards, those disclosed in U.S.Publication No. 2008/0166352 and PCT Publication No. WO 07/011941, whichare incorporated herein by reference in their entireties as to suchantibodies and related proteins, including but not limited to antibodiesdesignated therein as follow: 16H (having light chain variable and heavychain variable sequences SEQ ID NO:1 and SEQ ID NO:7 respectivelytherein); 5D (having light chain variable and heavy chain variablesequences SEQ ID NO:2 and SEQ ID NO:9 respectively therein); 2H (havinglight chain variable and heavy chain variable sequences SEQ ID NO:3 andSEQ ID NO:10 respectively therein); 43H (having light chain variable andheavy chain variable sequences SEQ ID NO:6 and SEQ ID NO:14 respectivelytherein); 41H (having light chain variable and heavy chain variablesequences SEQ ID NO:5 and SEQ ID NO:13 respectively therein); and 15H(having light chain variable and heavy chain variable sequences SEQ IDNO:4 and SEQ ID NO:12 respectively therein), each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing publication;

IL-15 specific antibodies, peptibodies, and related proteins, and thelike, such as, in particular, humanized monoclonal antibodies,particularly antibodies such as those disclosed in U.S. Publication Nos.2003/0138421; 2003/023586; and 2004/0071702; and U.S. Pat. No.7,153,507, each of which is incorporated herein by reference in itsentirety as to IL-15 specific antibodies and related proteins, includingpeptibodies, including particularly, for instance, but not limited to,HuMax IL-15 antibodies and related proteins, such as, for instance,14667;

IFN gamma specific antibodies, peptibodies, and related proteins and thelike, especially human IFN gamma specific antibodies, particularly fullyhuman anti-IFN gamma antibodies, such as, for instance, those describedin U.S. Publication No. 2005/0004353, which is incorporated herein byreference in its entirety as to IFN gamma specific antibodies,particularly, for example, the antibodies therein designated 1118;1118*; 1119; 1121; and 1121*. The entire sequences of the heavy andlight chains of each of these antibodies, as well as the sequences oftheir heavy and light chain variable regions and complementaritydetermining regions, are each individually and specifically incorporatedby reference herein in its entirety fully as disclosed in the foregoingpublication and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115. Inaddition, description of the properties of these antibodies provided inthe foregoing publication is also incorporated by reference herein inits entirety. Specific antibodies include those having the heavy chainof SEQ ID NO:17 and the light chain of SEQ ID NO:18; those having theheavy chain variable region of SEQ ID NO:6 and the light chain variableregion of SEQ ID NO:8; those having the heavy chain of SEQ ID NO:19 andthe light chain of SEQ ID NO:20; those having the heavy chain variableregion of SEQ ID NO:10 and the light chain variable region of SEQ IDNO:12; those having the heavy chain of SEQ ID NO:32 and the light chainof SEQ ID NO:20; those having the heavy chain variable region of SEQ IDNO:30 and the light chain variable region of SEQ ID NO:12; those havingthe heavy chain sequence of SEQ ID NO:21 and the light chain sequence ofSEQ ID NO:22; those having the heavy chain variable region of SEQ IDNO:14 and the light chain variable region of SEQ ID NO:16; those havingthe heavy chain of SEQ ID NO:21 and the light chain of SEQ ID NO:33; andthose having the heavy chain variable region of SEQ ID NO:14 and thelight chain variable region of SEQ ID NO:31, as disclosed in theforegoing publication. A specific antibody contemplated is antibody 1119as disclosed in the foregoing U.S. publication and having a completeheavy chain of SEQ ID NO:17 as disclosed therein and having a completelight chain of SEQ ID NO:18 as disclosed therein;

TALL-1 specific antibodies, peptibodies, and the related proteins, andthe like, and other TALL specific binding proteins, such as thosedescribed in U.S. Publication Nos. 2003/0195156 and 2006/0135431, eachof which is incorporated herein by reference in its entirety as toTALL-1 binding proteins, particularly the molecules of Tables 4 and 5B,each of which is individually and specifically incorporated by referenceherein in its entirety fully as disclosed in the foregoing publications;

Parathyroid hormone (“PTH”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,756,480, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind PTH;

Thrombopoietin receptor (“TPO-R”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,835,809, which is herein incorporated by reference in its entirety,particularly in parts pertinent to proteins that bind TPO-R;

Hepatocyte growth factor (“HGF”) specific antibodies, peptibodies, andrelated proteins, and the like, including those that target theHGF/SF:cMet axis (HGF/SF:c-Met), such as the fully human monoclonalantibodies that neutralize hepatocyte growth factor/scatter (HGF/SF)described in U.S. Publication No. 2005/0118643 and PCT Publication No.WO 2005/017107, huL2G7 described in U.S. Pat. No. 7,220,410 and OA-5d5described in U.S. Pat. Nos. 5,686,292 and 6,468,529 and in PCTPublication No. WO 96/38557, each of which is incorporated herein byreference in its entirety, particularly in parts pertinent to proteinsthat bind HGF;

TRAIL-R2 specific antibodies, peptibodies, related proteins and thelike, such as those described in U.S. Pat. No. 7,521,048, which isherein incorporated by reference in its entirety, particularly in partspertinent to proteins that bind TRAIL-R2;

Activin A specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. PublicationNo. 2009/0234106, which is herein incorporated by reference in itsentirety, particularly in parts pertinent to proteins that bind ActivinA;

TGF-beta specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. Pat. No.6,803,453 and U.S. Publication No. 2007/0110747, each of which is hereinincorporated by reference in its entirety, particularly in partspertinent to proteins that bind TGF-beta;

Amyloid-beta protein specific antibodies, peptibodies, related proteins,and the like, including but not limited to those described in PCTPublication No. WO 2006/081171, which is herein incorporated byreference in its entirety, particularly in parts pertinent to proteinsthat bind amyloid-beta proteins. One antibody contemplated is anantibody having a heavy chain variable region comprising SEQ ID NO:8 anda light chain variable region having SEQ ID NO:6 as disclosed in theforegoing publication;

c-Kit specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. Publication No.2007/0253951, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind c-Kit and/or otherstem cell factor receptors;

OX40L specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. Publication No.2006/0002929, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind OX40L and/or otherligands of the OX40 receptor; and

Other exemplary proteins, including Activase® (alteplase, tPA); Aranesp®(darbepoetin alfa); Epogen® (epoetin alfa, or erythropoietin); GLP-1,Avonex® (interferon beta-1a); Bexxar® (tositumomab, anti-CD22 monoclonalantibody); Betaseron® (interferon-beta); Campath® (alemtuzumab,anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade®(bortezomib); MLN0002 (anti-α4β7 mAb); MLN1202 (anti-CCR2 chemokinereceptor mAb); Enbrel® (etanercept, TNF-receptor/Fc fusion protein, TNFblocker); Eprex® (epoetin alfa); Erbitux® (cetuximab,anti-EGFR/HER1/c-ErbB-1); Genotropin® (somatropin, Human GrowthHormone); Herceptin® (trastuzumab, anti-HER2/neu (erbB2) receptor mAb);Humatrope® (somatropin, Human Growth Hormone); Humira® (adalimumab);insulin in solution; Infergen® (interferon alfacon-1); Natrecor®(nesiritide; recombinant human B-type natriuretic peptide (hBNP);Kineret® (anakinra); Leukine® (sargamostim, rhuGM-CSF); LymphoCide®(epratuzumab, anti-CD22 mAb); Benlysta™ (lymphostat B, belimumab,anti-BlyS mAb); Metalyse® (tenecteplase, t-PA analog); Mircera® (methoxypolyethylene glycol-epoetin beta); Mylotarg® (gemtuzumab ozogamicin);Raptiva® (efalizumab); Cimzia® (certolizumab pegol, CDP 870); Soliris™(eculizumab); pexelizumab (anti-C5 complement); Numax® (MEDI-524);Lucentis® (ranibizumab); Panorex® (17-1A, edrecolomab); Trabio®(lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4);Osidem® (IDM-1); OvaRex® (B43.13); Nuvion® (visilizumab); cantuzumabmertansine (huC242-DM1); NeoRecormon® (epoetin beta); Neumega®(oprelvekin, human interleukin-11); Neulasta® (pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF); Neupogen® (filgrastim, G-CSF,hu-MetG-CSF); Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonalantibody); Procrit® (epoetin alfa); Remicade® (infliximab, anti-TNFαmonoclonal antibody); Reopro® (abciximab, anti-GP IIb/IIia receptormonoclonal antibody); Actemra® (anti-IL6 Receptor mAb); Avastin®(bevacizumab), HuMax-CD4 (zanolimumab); Rituxan® (rituximab, anti-CD20mAb); Tarceva® (erlotinib); Roferon-A®-(interferon alfa-2a); Simulect®(basiliximab); Prexige® (lumiracoxib); Synagis® (palivizumab); 146B7-CHO(anti-IL15 antibody, see U.S. Pat. No. 7,153,507); Tysabri®(natalizumab, anti-α4integrin mAb); Valortim® (MDX-1303, anti-B.anthracis protective antigen mAb); ABthrax™; Vectibix® (panitumumab);Xolair® (omalizumab); ETI211 (anti-MRSA mAb); IL-1 trap (the Fc portionof human IgG1 and the extracellular domains of both IL-1 receptorcomponents (the Type I receptor and receptor accessory protein)); VEGFtrap (Ig domains of VEGFR1 fused to IgG1 Fc); Zenapax® (daclizumab);Zenapax® (daclizumab, anti-IL-2Rα mAb); Zevalin® (ibritumomab tiuxetan);Zetia® (ezetimibe); Orencia® (atacicept, TACI-Ig); anti-CD80 monoclonalantibody (galiximab); anti-CD23 mAb (lumiliximab); BR2-Fc (huBR3/huFcfusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti-TNFαmAb); HGS-ETR1 (mapatumumab; human anti-TRAIL Receptor-1 mAb);HuMax-CD20 (ocrelizumab, anti-CD20 human mAb); HuMax-EGFR (zalutumumab);M200 (volociximab, anti-α5β1 integrin mAb); MDX-010 (ipilimumab,anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1); anti-BR3 mAb; anti-C. difficileToxin A and Toxin B C mAbs MDX-066 (CDA-1) and MDX-1388); anti-CD22dsFv-PE38 conjugates (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC);anti-CD3 mAb (NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333(anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-CD40L mAb; anti-CriptomAb; anti-CTGF Idiopathic Pulmonary Fibrosis Phase I Fibrogen (FG-3019);anti-CTLA4 mAb; anti-eotaxin1 mAb (CAT-213); anti-FGF8 mAb;anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb(MYO-029); anti-GM-CSF Receptor mAb (CAM-3001); anti-HepC mAb (HuMaxHepC); anti-IFNα mAb (MEDI-545, MDX-1103); anti-IGF1R mAb; anti-IGF-1RmAb (HuMax-Inflam); anti-IL12 mAb (ABT-874); anti-IL12/1L23 mAb (CNTO1275); anti-IL13 mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC); anti-IL5Receptor mAb; anti-integrin receptors mAb (MDX-018, CNTO 95); anti-IP10Ulcerative Colitis mAb (MDX-1100); anti-LLY antibody; BMS-66513;anti-Mannose Receptor/hCGβ mAb (MDX-1307); anti-mesothelin dsFv-PE38conjugate (CAT-5001); anti-PD1mAb (MDX-1106 (ONO-4538)); anti-PDGFRαantibody (IMC-3G3); anti-TGβ mAb (GC-1008); anti-TRAIL Receptor-2 humanmAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR/Flt-1 mAb; anti-ZP3 mAb(HuMax-ZP3); NVS Antibody #1; and NVS Antibody #2.

Also included can be a sclerostin antibody, such as but not limited toromosozumab, blosozumab, or BPS 804 (Novartis). Further included can betherapeutics such as rilotumumab, bixalomer, trebananib, ganitumab,conatumumab, motesanib diphosphate, brodalumab, vidupiprant,panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX or XGEVA. Additionally,included in the device can be a monoclonal antibody (IgG) that bindshuman Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Such PCSK9specific antibodies include, but are not limited to, Repatha®(evolocumab) and Praluent® (alirocumab), as well as molecules, variants,analogs or derivatives thereof as disclosed in the following patents orpatent applications, each of which is herein incorporated by referencein its entirety for all purposes: U.S. Pat. Nos. 8,030,547, 8,563,698,8,829,165, 8,859,741, 8,871,913, 8,871,914, 8,883,983, 8,889,834,8,981,064, 9,056,915, 8,168,762, 9,045,547, 8,030,457, 8,030,457,8,829,165, 8,981,064, 8,030,457, U.S. Publication No. 2013/0064825, U.S.Patent Application Publication No. 2012/0093818, U.S. Patent ApplicationPublication No. 2013/0079502, U.S. Patent Application Publication No.2014/0357850, U.S. Patent Application Publication No. 2011/0027287, U.S.Patent Application Publication No. 2014/0357851, U.S. Patent ApplicationPublication No. 2014/0357854, U.S. Patent Application Publication No.2015/0031870, U.S. Patent Application Publication No. 2013/0085265, U.S.Patent Application Publication No. 2013/0079501, U.S. Patent ApplicationPublication No. 2012/0213797, U.S. Patent Application Publication No.2012/0251544, U.S. Patent Application Publication No. 2013/0072665, U.S.Patent Application Publication No. 2013/0058944, U.S. Patent ApplicationPublication No. 2013/0052201, U.S. Patent Application Publication No.2012/0027765, U.S. Patent Application Publication No. 2015/0087819, U.S.Patent Application Publication No. 2011/0117011, U.S. Patent ApplicationPublication No. 2015/0004174, U.S. Provisional Patent Application No.60/957,668, U.S. Provisional Patent Application No. 61/008,965, U.S.Provisional Patent Application No. 61/010,630, U.S. Provisional PatentApplication No. 61/086,133, U.S. Provisional Patent Application No.61/125,304, U.S. Provisional Patent Application No. 61/798,970, U.S.Provisional Patent Application No. 61/841,039, U.S. Provisional PatentApplication No. 62/002,623, U.S. Provisional Patent Application No.62/024,399, U.S. Provisional Patent Application No. 62/019,729, U.S.Provisional Patent Application No. 62/067,637, U.S. patent applicationSer. No. 14/777,371, International Patent Application No.PCT/US2013/048714, International Patent Application No.PCT/US2015/040211, International Patent Application No.PCT/US2015/056972, International Patent Application Publication No.WO/2008/057457, International Patent Application Publication No.WO/2008/057458, International Patent Application Publication No.WO/2008/057459, International Patent Application Publication No.WO/2008/063382, International Patent Application Publication No.WO/2008/133647, International Patent Application Publication No.WO/2009/100297, International Patent Application Publication No.WO/2009/100318, International Patent Application Publication No.WO/2011/037791, International Patent Application Publication No.WO/2011/053759, International Patent Application Publication No.WO/2011/053783, International Patent Application Publication No.WO/2008/125623, International Patent Application Publication No.WO/2011/072263, International Patent Application Publication No.WO/2009/055783, International Patent Application Publication No.WO/2012/0544438, International Patent Application Publication No.WO/2010/029513, International Patent Application Publication No.WO/2011/111007, International Patent Application Publication No.WO/2010/077854, International Patent Application Publication No.WO/2012/088313, International Patent Application Publication No.WO/2012/101251, International Patent Application Publication No.WO/2012/101252, International Patent Application Publication No.WO/2012/101253, International Patent Application Publication No.WO/2012/109530, and International Patent Application Publication No.WO/2001/031007, International Patent Application Publication No.WO/2009/026558, International Patent Application Publication No.WO/2009/131740, International Patent Application Publication No.WO/2013/166448, and International Patent Application Publication No.WO/2014/150983.

Also included can be talimogene laherparepvec or another oncolytic HSVfor the treatment of melanoma or other cancers. Examples of oncolyticHSV include, but are not limited to talimogene laherparepvec (U.S. Pat.Nos. 7,223,593 and 7,537,924); OncoVEXGALV/CD (U.S. Pat. No. 7,981,669);OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143);G207, 1716; NV1020; NV12023; NV1034 and NV1042 (Vargehes et al. (2002),Cancer Gene Ther., 9(12):967-978).

Also included are TIMPs. TIMPs are endogenous tissue inhibitors ofmetalloproteinases (TIMPs) and are important in many natural processes.TIMP-3 is expressed by various cells or and is present in theextracellular matrix; it inhibits all the major cartilage-degradingmetalloproteases, and may play a role in role in many degradativediseases of connective tissue, including rheumatoid arthritis andosteoarthritis, as well as in cancer and cardiovascular conditions. Theamino acid sequence of TIMP-3, and the nucleic acid sequence of a DNAthat encodes TIMP-3, are disclosed in U.S. Pat. No. 6,562,596, issuedMay 13, 2003, the disclosure of which is incorporated by referenceherein. Description of TIMP mutations can be found in U.S. PublicationNo. 2014/0274874 and PCT Publication No. WO 2014/152012.

Also included are antagonistic antibodies for human calcitoningene-related peptide (CGRP) receptor and bispecific antibody moleculethat target the CGRP receptor and other headache targets. Furtherinformation concerning these molecules can be found in PCT ApplicationNo. WO 2010/075238.

Additionally, a bispecific T cell engager antibody (BiTe), e.g.Blinotumomab can be used in the device. Alternatively, included can bean APJ large molecule agonist e.g., apelin or analogues thereof in thedevice. Information relating to such molecules can be found in PCTPublication No. WO 2014/099984.

In certain embodiments, the drug comprises a therapeutically effectiveamount of an anti-thymic stromal lymphopoietin (TSLP) or TSLP receptorantibody. Examples of anti-TSLP antibodies that may be used in suchembodiments include, but are not limited to, those described in U.S.Pat. Nos. 7,982,016, and 8,232,372, and U.S. Publication No.2009/0186022. Examples of anti-TSLP receptor antibodies include, but arenot limited to, those described in U.S. Pat. No. 8,101,182. Inparticularly preferred embodiments, the drug comprises a therapeuticallyeffective amount of the anti-TSLP antibody designated as A5 within U.S.Pat. No. 7,982,016.

While the present disclosure has been described in connection withvarious embodiments, it will be understood that the present disclosureis capable of further modifications. The present disclosure is intendedto cover any variations, uses, or adaptations of the disclosed subjectmatter following, in general, the principles of the present disclosure,and including such departures from the present disclosure as, within theknown and customary practice within the art to which the presentdisclosure pertains.

It is noted that the construction and arrangement of the drug deliverydevice and its various components and assemblies as shown in the variousexemplary embodiments is illustrative only. Although only a fewembodiments of the subject matter at issue have been described in detailin the present disclosure, those skilled in the art who review thepresent disclosure will readily appreciate that many modifications arepossible (e.g., variations in sizes, dimensions, structures, shapes andproportions of the various elements, values of parameters, mountingarrangements, use of materials, colors, orientations, etc.) withoutmaterially departing from the novel teachings and advantages of thesubject matter disclosed herein. For example, elements shown asintegrally formed may be constructed of multiple parts or elements, andvice versa. Also, the position of elements may be reversed or otherwisevaried, and the nature or number of discrete elements or positions maybe altered or varied. Accordingly, all such modifications are intendedto be included within the scope of the present disclosure as defined inthe appended claims. Furthermore, the order or sequence of any processor method steps may be varied or re-sequenced according to alternativeembodiments. Other substitutions, modifications, changes and omissionsmay be made in the design, operating conditions and arrangement of thevarious exemplary embodiments without departing from the scope of thepresent disclosure.

What is claimed is:
 1. A drug delivery device comprising: a housinghaving a bottom wall; an adhesive patch adhered to the bottom wall andhaving an area contained within an outer perimeter, the area having anupper surface, a lower surface, and an edge surface at the outerperimeter between the upper surface and the lower surface; a bacteriaimpermeable lower liner on the lower surface; and a bacteria impermeablesterility margin surrounding and abutting the edge surface of theadhesive patch, wherein the outer perimeter of the adhesive patch ispre-cut to separate from the sterility margin.
 2. The drug deliverydevice of claim 1, wherein the bacteria impermeable sterility margin isattached to or integral with the adhesive patch or the lower liner. 3.The drug delivery device of claim 1, further comprising a bacteriaimpermeable upper liner on the upper surface, wherein the sterilitymargin is optionally attached to or integral with the upper liner. 4.The drug delivery device of claim 1, wherein the outer perimeter of theadhesive patch is pre-cut in a perforated manner to separate from thesterility margin.
 5. The drug delivery device of claim 1, wherein thehousing includes an interior space and a top wall, a container isdisposed within the interior space, and the top wall includes a windowpositioned to allow viewing of the container, the window including apolarized filter that filters out up to and including 50% of light inthe visible range.
 6. An adhesive system for use with a wearable drugdelivery device, the system comprising: an adhesive patch having anouter perimeter, an upper surface, a lower surface, and an edge surfaceat the outer perimeter and extending between the upper surface and thelower surface; a bacteria impermeable lower liner on the lower surface;and a bacteria impermeable sterility margin surrounding and abutting theedge surface of the adhesive patch, wherein the outer perimeter of theadhesive patch is pre-cut to separate from the sterility margin.
 7. Theadhesive system of claim 6, wherein the bacteria impermeable sterilitymargin is attached to or integral with the adhesive patch or the lowerliner.
 8. The adhesive system of claim 6, further comprising a bacteriaimpermeable upper liner on the upper surface, wherein the sterilitymargin is optionally attached to or integral with the upper liner. 9.The adhesive system of claim 8, wherein the upper liner includes apre-cut first perimeter surrounding a portion of an area of the adhesivepatch that is configured to be adhered to a drug delivery device. 10.The adhesive system of claim 6, further comprising a hole provided inthe area to allow passage of a delivery member of the drug deliverydevice.
 11. The adhesive system of claim 6, wherein the outer perimeteris pre-cut in a perforated manner to separate from the sterility margin.12. The adhesive system of claim 6, wherein the sterility margin has awidth of at least two millimeters.